ABSTRACT Over the next 25 years, it is projected that over 72 million people will be 65 years and older in the United States representing 20% of the population. Age-related degeneration of the cranial muscles that culminate in reductions of muscle mass, strength, and function can contribute to swallowing deficits in over 15% of elderly people, negatively impacting health, nutrition, and quality of life. The tongue is crucial to adequate swallowing function. However, the processes primary to age-related decline in the cranial sensorimotor system have been understudied. Because swallowing disorders are so prevalent in the aging population, study of the underlying cellular mechanisms contributing to age-related muscular degeneration in the tongue is a clinical priority, as is the development of novel therapies that specifically target the pathways underlying these disorders. The proposed research will examine mechanisms that contribute to decline in satellite cell (SC; muscle-specific adult stem cells) regeneration and function, and the potential for an exercise-based treatment, similar to exercise tasks used now in the clinic, to reverse this age-induced cellular senescence. Specifically, we will study the effects of p16 expression, an aging biomarker associated with SC senescence in the limb, on SC activation, self-renewal, proliferation, and differentiation in aging rat lingual muscles. In addition, we will determine the immediate (2-week) and longer-term (8-week) effects of a tongue exercise treatment on p16 expression, SC regenerative capacity, and tongue muscle and swallowing function. We hypothesize that with age: (1) p16 expression will be up-regulated, (2) SC regenerative capacity will be reduced, and (3) tongue muscle and swallowing function will be impaired. With tongue exercise, we hypothesize that: (1) p16 expression will be down-regulated, (2) SC activation, self-renewal, proliferation, and differentiation will be enhanced following 2 weeks of exercise, (3) age-related reductions in SC regeneration will be rescued following 8 weeks of exercise, and (4) enhanced muscle regenerative processes will manifest in improved tongue muscle and swallowing function in aged rats. To address these hypotheses, this proposal has 2 specific aims: (1) to quantify putative underlying mechanisms of lingual muscle regeneration and tongue muscle SC populations in aging rats with and without exercise at multiple time points, (2) to determine the effects of age and exercise on tongue muscle and swallowing function. This research is highly significant because it is the first to examine the effects of the p16 aging biomarker on SC regenerative capacity and to isolate and quantify lingual muscle SCs with age and exercise, and determine whether improved SC regenerative processes manifest in functional gains. This proposal will be the first to elucidate and quantify underlying cellular mechanisms of age-related and exercise-induced muscle plasticity for the development of effective treatment and targeted delivery strategies for individuals with swallowing disorders.